This invention relates to a novel process for the preparation of 1-methylandrosta-1,4-diene-3,17-dione (Metandroden) and to the novel intermediates for this process. Metandroden is an inhibitor of estrogen biosynthesis (DOS No. 33 22 285; U.S. Pat. No. 4,591,585).
Heretofore, 1-methylandrosta-1,4-diene-3,17-dione has been prepared by oxidation of 17.beta.-hydroxyl-1-methylandrosta-1,4-dien-3-one (DOS No. 33 22 285) or by microbiological dehydrogenation of 1-methyl-15.alpha.-andros-1-ene-3,17-dione (DOS No. 35 12 328). The preparation methods for these two compounds themselves proceed by way of multi-stage syntheses and in low yields.
A problem that has not as yet been solved satisfactorily is the introduction of the .DELTA..sup.1 -double bond in the steroid having a 1.alpha.-methyl group and a .DELTA..sup.4 -double bond.
Thus far, the 1-methylandrosta-1,4-diene-3,17-dione system has been produced from the corresponding 17.beta.-hydroxyandrosta-1,4-dien-3-one via the synthesis sequence
(a) copper-catalyzed organometal Michael addition of a methyl anion (DAS No. 20 46 640), PA1 (b) hydrogenation of the .DELTA..sup.4 -double bond to the corresponding 5.alpha.-H-compound, PA1 (c) dibromination to the 2,4-dibromo steroid, PA1 (d) dual hydrogen bromide elimination, and PA1 (e) oxidation of the 17-alcohol to the 17-ketone (DOS No. 33 38 212 and DOS No. 35 39 244).
In this way of performing the synthesis, the already present .DELTA..sup.4 -double bond is hydrogenated (blocking group effect) and thereafter reintroduced together with the .DELTA..sup.1 -double bond.
This cumbersome process must be utilized because within the purview of the state of the art there is no suitable process known for evolving the 1-methylandrosta-1,4-diene-3,17-dione system directly from a 1.alpha.-methyl-4-androstene-3,17-dione.
The synthesis in accordance with the above-described synthesis sequence is furthermore made difficult by purification problems at the stage of dual hydrogen bromide elimination. The 2,4-dibromo-17.beta.-hydroxy-1.alpha.-methyl-5.alpha.-H-androstan-3-one reacts under the reaction condition to yield in addition to the desired 17.beta.-hydroxy-1-methylandrosta-1,4-dien-3-one, also the undesirable 17.beta.-hydroxy-1.alpha.-methylandrosta-4,6-dien-3-one in equal yields [J. Am. Chem. Soc. 68:1712 (1946) and Coll. Czech. Chem. Comm. 26:1852 (1961)]. This undesired by-product can be separated (chromatography) only with difficulties due to its similar properties.